In cancer chemotherapy the effectiveness of anticancer drugs is often limited by the resistance of tumor cells. Some tumors such as of the colon, pancreas, kidney and liver are generally innately resistant, and other responding tumors often develop resistance during the course of chemotherapy. The phenomena of multidrug resistance (MDR) is characterized by the tumor cells cross-resistance to adriamycin, daunomycin, vinblastine, vincristine, daxol, actinomycin D and etoposide. The resistance cells are often associated with overexpression of the mdrl gene. This gene product is a family of 140-220 kd trans-membrane phosphoglycoproteins (P-glycoprotein) which function as an ATP-dependent efflux pump. Thus, it has been postulated that this efflux mechanism keeps the intracellular level of the anticancer drug low, allowing the tumor cells to survive.
In recent years various substances such as verapamil, nifedipine and diltiazem have been used in in vitro experimental systems to reverse the MDR phenomena. More recently some of these agents have been tested clinically as MDR reversing agents. Little efficacy has been observed with verapamil or trifluoroperazine. Thus, there is a need for an effective MDR reversing agent.
2-Piperazino-4-morpholinothieno[3,2-d]pydmidines are reported in German Often. 2,055,085 [CA 77, 88539f (1972)].
Thienopyrimidines and pyridopyrimidines are claimed as gastric acid secretion inhibitors in European Patent Application 404,356 and 404,355, respectively.